B-cell lymphoma is a generally fatal cancer of the immune system. It afflicts about 100,000 people in the United States alone, and its incidence is increasing at about 7% per annum. This increase results in part from the corresponding increase in Acquired Immune Deficiency Syndrome ("AIDS"). The high grade B cell non-Hodgkin's lymphoma, which is a particularly aggressive lymphoma, is often a sequelae of AIDS; or HIV-1 infection.
By way of background, it is noted that malignant lymphomas are a heterogeneous group of neoplasms, generally originating in the lympho-reticular system. They are usually observed as lymph node tumors. Hodgkin's disease is a subgroup of the lymphomas. The cell of origin in Hodgkin's disease is believed to be derived from the monocyte-histiocyte series. The other lymphomas, which can affect either the T cell or the B cells, are referred to as non-Hodgkin's lymphomas. The non-Hodgkin's T and B cell lymphomas are divided into the high grade and low grade types, the former being more pathogenic than the latter.
Resting B cells, which are immunocompetent but not yet activated, express Igm and IgD. Once activated, these B cells can express any of the five immunoglobulin isotypes, (IgD, IgM, IgA, IgE or IgG). The non-Hodgkin's B cell lymphomas are generally associated only with B cells which express one particular isotype. IgM-expressing B cells are most often affected, leading to so-called small cleaved type lymphomas, characterized as such due to the appearance of the affected cells. However, B cells which express any of the other isotypes can also be affected.
Leukemia is best defined as the proliferation of a clone of abnormal hematopoietic cells. Myeloid leukemias affect the descendants of the myeloid lineage, whereas the lymphocytic leukemias involve abnormalities in the lymphoid lineage. The lymphocytic leukemias can be divided further into those affecting T cells and those affecting B cells. Leukemias of either type can be acute or chronic, the acute form being more aggressive. Without treatment, however, even the chronic leukemias can be fatal.
Several conventional methods are used to treat B cell lymphomas and leukemias. However, because these diseases respectively spread throughout the lymphatic and circulatory systems, conventional treatment is difficult. The tumors which arise in the B cell lymphomas are not amenable to removal by surgery. While radiation therapy may kill the individual lymphoma tumors, it will also damage the healthy tissue surrounding the malignancies.
Chemotherapy can be used to treat the B cell lymphomas or leukemias. The B cell leukemias are usually treated with chemotherapy because they do not produce readily identifiable tumors. The side effects of chemotherapy, however, are often debilitating, with damage to critical fast-growing cell such as blood cells in the bone marrow. Further, certain B cell lymphomas tend to rebound from chemotherapy in more aggressive forms.
Most B cell lymphomas (and, as noted above, substantially all the leukemias) are monoclonal, meaning that all tumor cells in a patient are derived from one cell, and therefore, bear the same antibody idiotype on the cell surface. This fact has led one group, IDEC Pharmaceuticals Corp., to attempt treatment of B cell lymphomas through targeting the affected B cells with antibodies which bind only to the idiotypes produced by the affected B cells. Typically, malignant cells derived from B cells at late stages of differentiation secrete antibody and also express antibody on their cell surface. The IDEC antibodies bind to both the secreted and cell-bound idiotypes. When the IDEC antibodies bind the cell-bound idiotypes, the associated B cells are somehow destroyed by the immune system's suppressive or cytolytic mechanism.
The IDEC approach avoids some disadvantages of conventional therapy, particularly the debilitating side effects of chemotherapy, but it also suffers from significant drawbacks. At first, it was necessary to custom-make the IDEC antibodies for each patient. It can take several months to make mouse (or reurine) antibodies. It is often desirable, however, to make chimeric or humanized antibodies which are less immunogenic than mouse antibodies. With aggressive high grade lymphomas, the patient would not survive long enough to produce the appropriate less immunogenic antibodies. Even with less aggressive, low grade lymphomas, the time to production is sufficiently long so that there could be an appreciable decline in the patient's health. Further, the production process is very labor intensive and expensive.
It was later discovered that certain tumor-associated idiotypes are common to some patients with B cell lymphoma. This meant that some of IDEC's antibodies would be effective among different patients. Even though it was then no longer necessary to custom make the product in all cases, several disadvantages remained.
First, the developers of the IDEC therapy have recognized that it is only effective in patients which secrete limited amounts of the target antibodies. See S.L. Brown et al., "Antiidiotype Antibody Therapy of B-Cell Lymphoma" Vol. 16, No. 3, pp. 199-210 Seminars in Oncology (June 1989). In patients which secrete large amounts of antibody, much of the IDEC antibodies which are -administered will bind to these endogenous secreted antibodies, and thus, the administered antibodies will not significantly affect the tumorous B cells. It is known that the tumorous B cells in patients having high grade lymphomas, and who are particularly in need of an immediately effective treatment, secrete large amounts of antibody. Thus, the IDEC therapy may be least effective in those who need it most.
The S.L. Brown et al. group also recognized that the IDEC therapy selects for idiotype-negative tumor cells. These tumor cells do not react with the IDEC antibodies, resulting in new tumors which cannot be treated with the IDEC methods. This group also combined the IDEC therapy with administration of l@ba interferon. This appeared to yield a higher response rate than antibody administration alone, yet it also appeared to exert an even stronger selection pressure for the idiotype-negative tumor cells.
In an alternative approach, some members of this group tried using a radiolabeled antibody to target the tumor cells. The radiolabeled antibody is itself cytotoxic. One disadvantage noted by this group is that myelosuppression occurred in all patients tested three to five weeks after treatment. An additional disadvantage of this therapy which was not noted is inherent in the use of radioisotopes. The patient's feces, urine, saliva, sweat, and other bodily secretions will all become radioactive as a result of the treatment. Disposal of these radioactive products presents major problems.
It seems that administering antibodies which react only with cell-bound idiotypes, which idiotypes are common to a majority of patients and are not subject to selection which yields an idiotype-negative tumor cell, would be an effective therapy for both B cell lymphoma and B cell leukemia. Such antibodies would avoid the disadvantages of radioimmunotherapy, chemotherapy, and of the IDEC approach.